Organic contrast agent analog and method of making same

ABSTRACT

An organic contrast agent analog is derived to contain fluorine moieties. A method for making the organic contrast agent analog includes the steps of fluorinating the contrast agent analog for increasing the acidity of the analog to increase the choleretic activity of the analog and to render it less toxic.

This is a continuation of U.S. patent application Ser. No. 07/500,471,filed Mar. 28, 1990, now U.S. Pat. No. 5,143,715.

TECHNICAL FIELD

The present invention relates to organic contrast agent analogs andmethods of making the analogs. More particularly, the present inventionrelates to a method of decreasing the toxicity of such agents throughchemical modification.

BACKGROUND ART

In general, current cholangiographic agents used as biliary X-raycontrast agents are now considered too toxic to meet risk/benefitcriteria for routine use as contrast agents to visualize the biliarysystem. Because of the relative toxicity of these agents, these agentsare being replaced in use by alternative imaging methodologies, such asultrasound and magnetic resonance imaging (MRI). On the other hand, theresolution achievable with X-ray radiology techniques is superb.Accordingly, biliary contrast agents can still be quite useful.

A second issue with regard to these agents is the low rate of choleresisassociated with biliary excretion of the agent. The low rate ofcholeresis increases the biliary concentration and thus increases thetoxicity.

Current biliary X-ray contrast agents have amphophilic properties. Theseagents have a hydrophilic head portion; that is, the --CO₂ H terminus,and a hydrophobic tail; that is, triiodo aniline moiety with anunsubstituted 5-position. Because of this property, they are excretednearly exclusively by the biliary route. Typical of most amphilphilicmolecules, these biliary contrast agents tend to self associate. Thisproperty is reflected by the low critical micellar concentration and lowosmolalities of their aqueous salt solution.

It is therefore desirable to produce a less toxic and more cholereticcontrast agent.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided an organiccontrast agent analog wherein the analog is an oral or intravenous mediahaving the formula I: ##STR1##

    __________________________________________________________________________              R.sub.1          R.sub.2                                            __________________________________________________________________________    Iopanoic acid                                                                            ##STR2##        NH.sub.2                                           Ipodatic acid                                                                           CH.sub.2 CH.sub.2 COOH                                                                         NCHN(CH.sub.3).sub.2                               Tyropanoic acid                                                                          ##STR3##        NHCOCH.sub.2 CH.sub.2 CH.sub.3                     Iocetamic acid                                                                           ##STR4##        NH.sub.2                                           Iopronic acid                                                                            ##STR5##        NHCOCH.sub.3                                       Iosumetic acid                                                                           ##STR6##        NHCH.sub.3                                         __________________________________________________________________________

or wherein said analog is an intravenous media having formula II;##STR7## and R₃ is

    ______________________________________                                                  R.sub.3                                                             ______________________________________                                        Iodipamide  NHCO(CH.sub.2).sub.4 CONH                                         Ioglycamide NHCOCH.sub.2 OCH.sub.2 CONH                                       Iodoxamate  NHCO(CH.sub.2 CH.sub.2 O).sub.4 CH.sub.2 CH.sub.2 CONH            Iotroxamide NHCO(CH.sub.2 OCH.sub.2).sub.3 CONH                               Iosulamide* NHCOCH.sub.2 CH.sub.2 SO.sub.2 CH.sub.2 CH.sub.2 CONH             ______________________________________                                         ##STR8##                                                                     -  or wherein said analog is an urographic media having formula III;           ##STR9##     wherein the analog includes one or more fluorine substitutions or     additions.

The present invention further provides a method of making the organiccontrast agent analog including the steps of forming the organiccontrast agent analog having formulas I, II, or III and substituting oradding at least one flourine moiety to the analog.

FIGURES IN THE DRAWINGS

Other advantages of the present invention will be readily appreciated asthe same becomes better understood by reference to the followingdetailed description when considered in connection with the accompanyingdrawings wherein:

FIGS. 1 and 2 are high resolution NMR proton spectrums;

FIG. 3 is a high resolution NMR fluorine spectrum;

FIGS. 4 and 5 are mass spectrum analyses performed on TFA-IOP made inaccordance with the present invention;

FIG. 6 is a plotted curve comparing biliary concentration over time ofIOP versus TFA-IOP;

FIG. 7 is comparative data of TFA-IOP and IOP plasma concentrationversus time; and

FIG. 8 is a comparative date of TFA-IOP and IOP biliary excretionconcentration versus time.

DESCRIPTION OF THE INVENTION

Generally, an organic contrast agent analog made in accordance with thepresent invention has the following general formula I: ##STR10## and R₁and R₂ are

    __________________________________________________________________________              R.sub.1          R.sub.2                                            __________________________________________________________________________    Iopanoic acid                                                                            ##STR11##       NH.sub.2                                           Ipodatic acid                                                                           CH.sub.2 CH.sub.2 COOH                                                                         NCHN(CH.sub.3).sub.2                               Tyropanoic acid                                                                          ##STR12##       NHCOCH.sub.2 CH.sub.2 CH.sub.3                     Iocetamic acid                                                                           ##STR13##       NH.sub.2                                           Iopronic acid                                                                            ##STR14##       NHCOCH.sub.3                                       Iosumetic acid                                                                           ##STR15##       NHCH.sub.3                                         __________________________________________________________________________

or wherein said analog is an intravenous media having the formula II;##STR16## and R₃ is

    ______________________________________                                                  R.sub.3                                                             ______________________________________                                        Iodipamide  NHCO(CH.sub.2).sub.4 CONH                                         Ioglycamide NHCOCH.sub.2 OCH.sub.2 CONH                                       Iodoxamate  NHCO(CH.sub.2 CH.sub.2 O).sub.4 CH.sub.2 CH.sub.2 CONH            Iotroxamide NHCO(CH.sub.2 OCH.sub.2).sub.3 CONH                               Iosulamide* NHCOCH.sub.2 CH.sub.2 SO.sub.2 CH.sub.2 CH.sub.2 CONH             ______________________________________                                         ##STR17##                                                                    -  or wherein said analog is an urographic media having the formula III;       ##STR18##

The agent includes a hydrophilic head (side chain) and a hydrophilictail (benzine ring). The fluorine addition or substitution providesmeans for increasing the acidity of the agent and increasing thecholeretic activity of the agent to render the agent less toxic.

Examples of oral cholecystographic contrast media which can be modifiedin accordance with the present invention are

                                      TABLE 1                                     __________________________________________________________________________              proprietary     Molecular weight(m.w.)                                                                    Iodine                                  Common name                                                                             name     Manufacturer                                                                         Acid form                                                                           Salt form                                                                           (%/m.w.)                                __________________________________________________________________________    Iopanoic acid                                                                           Telepaque                                                                              Winthrop                                                                             571         66.7                                    Ipodate.calcium                                                                         Oragratin.calcium                                                                      Squibb 598   1.234 63.7                                    Ipodate.sodium                                                                          Oragratin.sodium                                                                       Squibb 598   620   63.7                                    Tyropanoate.sodium                                                                      Bilopaque                                                                              Winthrop                                                                             641   663   59.4                                    Iocetamic acid                                                                          Cholebrine                                                                             Mallinckrodt                                                                         614         62.0                                    Iopronic acid                                                                           Oravue   Squibb 673         56.6                                    Iosumetic acid     Schering                                                                             628         60.6                                    __________________________________________________________________________

Examples of intravenous cholangiographic media modifiable in accordancewith the present invention are

                                      TABLE 2                                     __________________________________________________________________________    N-Methylglucamine salt                                                                    Proprietary   Molecular weight(m.w.)                                                                    Iodine                                  or contrast media                                                                         name   Manufacturer                                                                         Acid form                                                                           Salt form                                                                           (%/m.w.)                                __________________________________________________________________________    Iodipamide  Chologratin                                                                          Squibb 1.140 1.530 66.8                                    Ioglycamide Biligram                                                                             Schering                                                                             1.128 1.518 67.5                                    Iodoxamate  Cholevue                                                                             Winthrop                                                                             1.288 1.678 59.1                                    Iotroxamide        Schering                                                                             1.316 1.706 57.9                                    Iosulamide         Winthrop                                                                             1.376 1.764 55.3                                    __________________________________________________________________________

More specifically, the starting agent can be a cholangiographic orcholecystographic agent as stated above. The agent can be of the oral orintravenous types. That is, the agent is iodinated such that it can beused as a biliary X-ray contrast agent for routine use to visualizehepatocytes gallbalder and the the biliary system. Unlike previouslyused cholecystographic agents, such as underivatized iopanoic acid, thepresent invention is a chemically modified organic contrast agent analogwhich is rendered less toxic and more choleretic by the modification ofthe agent including additional fluorine functionalities on the agent,the fluorine functionalities rendering the agent more acidic and morecholeretic.

It has been hypothesized that if an amphophilic molecule, such as acommon organic contrast agent analog is rendered a stronger acid and isfully or at least more disassociated at physiological pH, it will mostlikely be excreted unconjugated, without causing choloresis and withoutbeing trapped in the intrahepatic shunt pathway (Sawkat, MS. et al;Influence of side-chain charge on hepatic transport of bile acids andbile acid analogues. American Journal Physiology 249:G479-G488, 1985;Gurantz D., et al; Influence of bile acid structure on bile flow andbiliary lipid secretion in the hamster. American Journal Physiology247:G738-G748, 1984; Yoon, YB, et al, Effect of side-chain shortening onthe physiologic properties of bile acids: hepatic transport and effecton biliary sectetion of 23-nor-ursodeoxycholate in rodents.Gastroenterology 90:837-852, 1986). Even in the presence of choleresis,if the hepatocyte and canalicular transport steps are rapid, the biliarycontrast agent is expected to move as a bolus, and anatomical details,such as the intrahepatic ducts, can be visualized in patients with goodhepatocyte function.

For example, the agent can be N-trifluoroacetyl-iopanoic acid oralpha-fluoro-N-trifluoroacidic-iopanoic acid.

The present invention further provides a method of making the organiccontrast agent analog. The method generally includes the steps offorming the organic contrast agent analog having the formulas I, II, orIII and then increasing the acidity of the agent while increasing thecholeretic activity of agent to render the agent less toxic by adding orsubtituting flourine on the agent.

EXPERIMENTS

1. Synthesis of N-trifluoro Derivative

of Iopanoic Acid

Three fluorine atoms were attached to the cholecystographic agentiopanoic acid (IOP) so that it could be detected using 19-F magneticresonance techniques.

IOP was reacted with trifluoroacetic anhydride at 0° C. intetrahydrofuran. After the reaction was complete, the organic solventswere removed. The residue was dissolved in ethyl acetate and washedtwice with water. The organic layer was dried over magnesium sulphateand the solvent was removed to obtain the final product. The product,N-trifluorcacetyl iopanoic acid, had a melting point of 193° C. and anextension coefficient of approximately 37,000 at 232 nm. The assignedstructure was verified using high resolution proton and fluorine NMRspectroscopy, elemental analysis and mass spectrum analysis. Theisolated yield of the product was 97.5%.

The following summarizes the reaction. ##STR19## 2. Synthesis ofAlpha-fluoro-N-trifluoroacetyl-Iopanoic Acid

Functional groups were placed on the carbon atom alpha to the carboxylgroup of the organic contrast agent, iopanoic acid. A fluorine atom wasplaced on the carbon atom alpha to the carboxyl group ofN-trifluoroacetyl-iopanoic acid to significantly effect its pKa andthus, effect its biodistribution and metabolism. The followingsummarizes the synthesis of the alpha-fluoro-N-trifluoroacetyliopanoicacid. ##STR20##

Results of elemental analysis of TFA-IOP provided by GalbraithLaboratories, Inc., Knoxville, Tenn. are as follows:

    ______________________________________                                        Galbraith        Theoretical                                                                             Error                                              ______________________________________                                        C      24.33%        24.03%    +0.30%                                         H      1.93%         2.15%     -0.22%                                         N      2.04%         2.00%     +0.04%                                         F      8.50%         8.15%     -0.35%                                         I      55.24%        54.51%    +0.73%                                         O                    9.16%                                                                         100.0%                                                   ______________________________________                                    

The calculations are based on the inclusion of a molecule of methanolwith each molecule of TFA-IOP.

High resolution NMR proton spectrums (FIGS. 1 and 2), high-resolutionNMR fluorine spectrum (FIG. 3) and mass spectrum analyses (FIGS. 4 and5) were performed on TFA-IOP. The results of each confirm the expectedchemical structure of the new compound. Mass spectral analysis wasperformed.

3. Comparative Data of Biliary Excretion of IOP and Trifluoroacetyl IOP

Experiments were conducted to compare the biodistribution and excretionof TFA-IOP to that of the parent compound IOP. TFA-IOP and IOP were eachadministered intravenously to rats (100 umol/kg) in order to compare thebiodistribution and excretion of the compound made in accordance withthe present invention and the parent compound. Tissues examined includedliver, spleen, upper GI, lower GI, kidney, lung and heart. The length ofeach study was 90 minutes, during which time bile, urine and plasmasamples were taken to monitor uptake and excretion. NMR relaxation ratesfor liver and plasma were also examined to note whether uptake of eithercompound might possible alter these parameters.

4. Results

In general, liver concentrations 90 minutes post injection were 512 uMand 202 uM after IOP and TFA-IOP injection, respectively, while kidneyconcentrations were 105 uM and 5 uM. Lesser concentrations were found inthe other tissues. Excretion of the two compounds were found only inbile with no compound detected in urine. In bile, TFA-IOP reached amaximum concentration of 0.5 uM with the recovery of 40% of theinjection dose during a 90 minute time period (see FIG. 6). For IOP, thebiliary concentration reached 10 mM with 18% of the injected doesrecovered during the 90 minute collection period as shown in FIG. 6.Plasma disappearance curves were similar in form, as shown in FIG. 7.Thin layer chromatoqraphy of bile indicated that a vast majority of theinjected TFA-IOP was metabolized to a single metabolite. Nononmetabolized compound was found.

These results indicate that TFA and IOP are similar to theirbiodisposition except the rate of biliary excretion of TFA-IOP appearsto be approximately twice that of IOP, as shown in FIG. 8.

Tables 1 through 5 summarizes the results of each experiment conducted.Table 6 shows a more detailed analysis of the tissue concentrationresults with values such as total micromoles in tissue, percent ofdose/gm, etc.

Tables 7 and 8 contain analysis of the bile excretion results.

                  TABLE 1                                                         ______________________________________                                        TISSUES:                                                                               -IOP CONCENTRATION (uM)                                                       90 MIN POST INJECTION                                                         I-6   % OF      I-8       % OF                                                (IOP) DOSE      (TFA-IOP) DOSE                                       ______________________________________                                        LIVER      511.90  14.53     201.73  6.04                                     KIDNEY     105.40  0.69      57.84   0.34                                     *UPPER GI  307.81  1.31      140.23  0.41                                     *LOWER GI  135.23  0.59      178.09  0.63                                     *SPLEEN    255.54  0.45      164.06  0.24                                     *LUNG      324.91  1.21      277.64  0.83                                     *HEART     259.38  0.72      242.85  0.72                                     ______________________________________                                         No standard curves were compiled for these tissues. The values given          represent concentrations generated using the LIVER analysis routine and       standard curve. Because this routine utilizes a control LIVER spectra for     background modeling, erroneous Iodine concentration values for these          tissues may result due to inappropriate background removal.              

                  TABLE 2                                                         ______________________________________                                        PLASMA:                                                                                 -IOP CONCENTRATION (uM)                                             SAMPLING    I-6         I-8                                                   TIME (min)  (IOP)       (TFA-IOP)                                             ______________________________________                                         0          ****         0.00                                                 10          ****        863.19                                                20          ****        603.93                                                30          556.68      573.38                                                40          ****        510.22                                                50          507.76      469.19                                                60          462.07      414.69                                                70          462.46      373.79                                                80          403.95      403.05                                                90          372.89      359.94                                                ______________________________________                                         ****Indicates that no samples were obtained for these time periods.      

                  TABLE 3                                                         ______________________________________                                        BILE:                                                                                   -IOP CONCENTRATION (uM)                                             SAMPLING    I-6         I-8                                                   TIME (min)  (IOP)       (TFA-IOP)                                             ______________________________________                                         0          ****         635.0                                                 5          1605.8      3010.0                                                15          8659.4      5777.6                                                25          10504.9     6436.1                                                35          9854.3      7802.9                                                45          9667.6      7641.1                                                55          7316.4      8461.4                                                65          7529.1      5372.5                                                75          7758.8      5305.7                                                85          9564.6      4663.1                                                ______________________________________                                         ****Indicates that no sample was obtained for this time period.          

                  TABLE 4                                                         ______________________________________                                        URINE:                                                                                  -IOP CONCENTRATION (uM)                                             SAMPLING    I-6         I-8                                                   TIME (min)  (IOP)       (TFA-IOP)                                             ______________________________________                                         0-20       0           0                                                     20-40       0           0                                                     40-60       0           ***                                                   60-80       0           ***                                                   80-90       0           ***                                                   ______________________________________                                         ***Indicates that no samples were obtained for these time periods.       

                  TABLE 5                                                         ______________________________________                                        NMR DATA:                                                                              CONTROL       I-6      I-8                                           TISSUE   VALUE         (IOP)    (TFA-IOP)                                     ______________________________________                                               T1 VALUES (msec)                                                       Liver    214.96        228.26   243.07                                        Plasma   1332.65       1406.19  1455.34                                              T2 VALUES (msec)                                                       Liver     38.27         28.65    28.94                                        Plasma   232.18        257.87   221.56                                        ______________________________________                                         As expected, the values obtained do not significantly differ from control     values                                                                   

                                      TABLE 6                                     __________________________________________________________________________                     uMOLES           PERCENTAGE OF DOSE                                 TISSUE                                                                              % OF      PER              PER                                          WEIGHT                                                                              B. WT.                                                                            IN TISS.                                                                            gram kg    IN TISS.                                                                            gram kg b.wt.                         __________________________________________________________________________    INTRAVENOUS IOP RAT STUDY                                                     RAT NUMBER: 6                                                                 DOSE: 104. umoles/kg                                                          TIME: 90. minutes                                                             BODY WEIGHT: 406. grams                                                       LIVER  11.98 2.95                                                                              6.13  .51  511.90                                                                              14.52 1.21 35.77                            SPLEEN .75   .18 .19   .26  255.54                                                                              .45   .61  1.12                             UPPER GI                                                                             1.79  .44 .55   .31  307.91                                                                              1.31  .73  3.22                             LOWER GI                                                                             1.83  .45 .25   .14  135.23                                                                              .59   .32  1.44                             KIDNEY 2.76  .68 .29   .11  105.40                                                                              .69   .25  1.70                             LUNG   1.57  .39 .51   .32  324.91                                                                              1.21  .77  2.98                             HEART  1.18  .29 .31   .26  259.38                                                                              .72   .61  1.79                             INTRAVENOUS TFA-IOP RAT STUDY                                                 RAT NUMBER: 8.                                                                DOSE: 100. umoles/kg                                                          TIME: 90. minutes                                                             BODY WEIGHT: 435. grams                                                       LIVER  13.02 2.99                                                                              2.63  .20  201.73                                                                              6.04  .46  13.88                            SPLEEN .63   .14 .10   .16  164.06                                                                              .24   .38  .55                              UPPER GI                                                                             1.27  .29 .18   .14  140.23                                                                              .41   .32  .94                              LOWER GI                                                                             1.54  .35 .27   .18  178.09                                                                              .63   .41  1.45                             KIDNEY 2.56  .59 .15   .06   57.84                                                                              .34   .13  .78                              LUNG   1.30  .30 .36   .28  277.64                                                                              .83   .64  1.91                             HEART  1.29  .30 .31   .24  242.85                                                                              .72   .56  1.66                             __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________    INTRAVENOUS TFA-IOP RAT STUDY                                                 RAT I.D.: I-8                                                                 COMPOUND: TFA-IOP                                                             DOSE: 100. umoles/kg                                                          BODY WEIGHT: 435. grams                                                       UMOLES INJECTED: 43.50 umoles                                                 LIVER WEIGHT: 13.02 grams                                                     EXP. LENGTH: 90 minutes                                                       __________________________________________________________________________    SAMPLE                                                                              BILE FLOW   COMPOUND                                                                              EXCRETION     SAMPLE                                PERIOD                                                                              ml/ ml/min PER                                                                            CONC.   umoles/                                                                            umoles/min PER                                                                         WEIGHT                                (min) min kg b.w.                                                                           kg l.w.                                                                           (umolar)                                                                              min  kg b.w.                                                                           kg l.w.                                                                            (grams)                               __________________________________________________________________________    10-0  .02093                                                                            .04811                                                                            1.60753                                                                            635.0  .013 .031                                                                               1.021                                                                             .20930                                 0-10 .04071                                                                            .09359                                                                            3.12673                                                                           3010.0  .123 .282                                                                               9.411                                                                             .40710                                10-20 .03675                                                                            .08448                                                                            2.82258                                                                           5777.6  .212 .488                                                                              16.308                                                                             .36750                                20-30 .04050                                                                            .09310                                                                            3.11060                                                                           6436.1  .261 .599                                                                              20.020                                                                             .40500                                30-40 .02992                                                                            .06878                                                                            2.29800                                                                           7802.9  .233 .537                                                                              17.931                                                                             .29928                                40-50 .03047                                                                            .07005                                                                            2.34025                                                                           7641.1  .233 .535                                                                              17.882                                                                             .30470                                50-60 .02817                                                                            .06476                                                                            2.16359                                                                           8461.4  .238 .548                                                                              18.307                                                                             .28170                                60-70 .02721                                                                            .06255                                                                            2.08986                                                                           5372.5  .146 .336                                                                              11.228                                                                             .27210                                70-80 .02653                                                                            .06099                                                                            2.03763                                                                           5305.7  .141 .324                                                                              10.811                                                                             .26530                                80-90 .02586                                                                            .05945                                                                            1.98618                                                                           4663.1  .121 .277                                                                               9.262                                                                             .25860                                __________________________________________________________________________    SAMPLE UMOLES       PERCENTAGE OF DOSE                                        PERIOD IN    RUNNING                                                                              IN    RUNNING                                                                              PER gm.                                                                             PER kg.                                (min)  SAMPLE                                                                              TOTAL  SAMPLE                                                                              TOTAL  SAMPLE                                                                              BODY WT.                               __________________________________________________________________________    10-0    .13   .13    .31   .31    1.46 .70                                     0-10  1.23   1.36  2.82   3.12   6.92 6.48                                   10-20  2.12   3.48  4.88   8.00  13.28 11.22                                  20-30  2.61   6.09  5.99  14.00  14.80 13.78                                  30-40  2.33   8.42  5.37  19.36  17.94 12.34                                  40-50  2.33  10.75  5.35  24.71  17.57 12.30                                  50-60  2.38  13.13  5.48  30.19  19.45 12.60                                  60-70  1.46  14.60  3.36  33.56  12.35 7.73                                   70-80  1.41  16.00  3.24  36.79  12.20 7.44                                   80-90  1.21  17.21  2.77  39.56  10.72 6.37                                   __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________    INTRAVENOUS IOP RAT STUDY                                                     RAT I.D.: I-6                                                                 COMPOUND: IOP                                                                 DOSE: 104. umoles/kg                                                          BODY WEIGHT: 406. grams                                                       UMOLES INJECTED: 42.22 umoles                                                 LIVER WEIGHT: 11.98 grams                                                     EXP. LENGTH: 90 minutes                                                       __________________________________________________________________________    SAMPLE BILE FLOW       COMPOUND  EXCRETION                                    PERIOD ml/  ml/min PER CONC.     umoles/                                                                             umoles/min PER                         (min)  min  kg b.w.                                                                             kg l.w.                                                                            (umolar)  min   kg b.w.                                                                             kg l.w.                          __________________________________________________________________________    -10-0  no sample weight                                                                              no sample conc.                                          0-10 .01375                                                                             .03386                                                                              1.14750                                                                            1605.8    .022  .054  1.843                             10-20 .00867                                                                             .02136                                                                              .72404                                                                             8659.4    .075  .185  6.270                             20-30 .01077                                                                             .02652                                                                              .89866                                                                             10504.9   .113  .279  9.440                             30-40 .00977                                                                             .02406                                                                              .81528                                                                             9854.3    .096  .237  8.034                             40-50 .01161                                                                             .02861                                                                              .96953                                                                             9667.6    .112  .277  9.373                             50-60 .00904                                                                             .02225                                                                              .75417                                                                             7316.4    .066  .163  5.518                             60-70 .01072                                                                             .02640                                                                              .89457                                                                             7529.1    .081  .199  6.735                             70-80 .01018                                                                             .02506                                                                              .84942                                                                             7758.8    .079  .194  6.590                             80-90 .00977                                                                             .02407                                                                              .81586                                                                             9564.6    .093  .230  7.803                            __________________________________________________________________________    SAMPLE                                                                              SAMPLE                                                                               UMOLES      PERCENTAGE OF DOSE                                   PERIOD                                                                              WEIGHT                                                                              IN    RUNNING                                                                              IN    RUNNING                                                                              PER gm.                                                                             PER kg.                           (min) (grams)                                                                             SAMPLE                                                                              TOTAL  SAMPLE                                                                              TOTAL  SAMPLE                                                                              BODY WT.                          __________________________________________________________________________    -10-0 no sample concentration, thus cannot calculate these values               0-10                                                                              .13747                                                                              .22   .22    .52   .52    3.80  1.29                               10-20                                                                              .08674                                                                              .75   .97    1.78  2.30   20.51 4.38                               20-30                                                                              .10766                                                                              1.13  2.10   2.68  4.98   24.88 6.60                               30-40                                                                              .09767                                                                              .96   3.07   2.28  7.26   23.34 5.61                               40-50                                                                              .11615                                                                              1.12  4.19   2.66  9.92   22.98 6.55                               50-60                                                                              .09035                                                                              .66   4.85   1.57  11.48  17.33 3.86                               60-70                                                                              .10717                                                                              .81   5.66   1.91  13.40  17.83 4.71                               70-80                                                                              .10176                                                                              .79   6.45   1.87  15.27  18.38 4.61                               80-90                                                                              .09774                                                                              .93   7.38   2.21  17.48  22.65 5.45                              __________________________________________________________________________

What is claimed is:
 1. A modified organic contrast analog, comprisingalpha-fluoro-N-trifluoroacetyl-iopanoic acid.